Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• This disclosure is in the field of pharmaceutical chemistry.
• this disclosure relates to 3,5-disubstituted pyrazole compounds, and their uses as therapeutically effective kinase inhibitors and anticancer agents.
• the growth and proliferation of eukaryotic cells go through a process referred to as mitosis to divide to two daughter cells with identical genetic information of the mother cell.
• a cell proliferation and division process is called cell cycle.
• the cell cycle consists of four phases: G1 phase in which a great deal of proteins, RNAs and the like are synthesized to prepare cell for DNA synthesis; S phase in which DNAs are replicated; G2 phase as the preparation stage before the mitosis, in this phase cell will make sure that the DNA replication is accurate; and M phase in which mitosis takes place.
• G1 phase in which a great deal of proteins, RNAs and the like are synthesized to prepare cell for DNA synthesis
• S phase in which DNAs are replicated
• G2 phase as the preparation stage before the mitosis, in this phase cell will make sure that the DNA replication is accurate
• M phase in which mitosis takes place.
• DDR DNA-damage-response
• cell cycle checkpoints are also activated, which includes G1/S checkpoint, Intra-S or S checkpoint and G2/M checkpoint to prevent cell from entering mitosis (Lobrich M et al. Nature reviews Cancer 2007,7 (11): 861-869).
• DDR pathway is activated and a series of complex mechanisms mediate the detection and repair of the damaged DNA.
• Cell cycle checkpoint kinase CHK1 and CHK2 play very important roles in DDR pathway.
• CHK1 protein a serine/threonine kinase (Sanchez Yet al., Science, 1997, 277(5331): 1497-1501), is a core component of cell cycle regulation especially the G2/M checkpoint ATR-CHK1-CDC25C axis.
• ATR When a DNA damage signal is recognized ATR is activated, ATR in turn phosphorylates CHK1 at multiple serine sites to activate CHK1. The activated CHK1 further phosphorylates downstream CDC25 and causes CDC25 degradation.
• CHK1 protein kinase is highly expressed in various cancer cells including breast cancer, colon cancer, liver cancer and gastric cancer. The insensitivity or resistance of some cancer cells to chemotherapy, radiotherapy and other anticancer agents is often associated with the over activation of CHK1 (Bao S et al., Nature 2006, 444 (7120): 756-760).
• One of the hot areas in anticancer research is to regulate cell cycle checkpoint such as inhibiting CHK1 kinase to promote cancer cell apoptosis. This is the scientific foundation to explore CHK1 inhibitors as anti-cancer agents.
• CHK1 kinase inhibitors with various structures have been disclosed.
• WO03/10444 and WO2005/072733 have disclosed aryl/heteroaryl urea compounds as CHK1 kinase inhibitors
• WO02/070494, WO2006/021002, WO2006/105262 and WO2006/014359 have disclosed substituted urea compounds as CHK1 kinase inhibitors
• WO2005/009435, WO2010/077758, WO2012/064548, WO2015/120390 and WO2017/132928 have disclosed substituted pyrazole compounds as CHK1 kinase inhibitors.
• the disclosure provides novel 3,5-disubstituted pyrazole compounds of Formulae I, IIa, IIb, III and IV or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates or prodrugs thereof, as kinase inhibitors, especially as CHK1 kinase inhibitors.
• compositions comprising an effective amount of the compounds of Formula I, IIa, IIb, III or IV or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates or prodrugs thereof, for the treatment of cancer.
• the pharmaceutical composition may also comprise one or more pharmaceutically acceptable carriers or diluters, for the treatment of cancer.
• the pharmaceutical composition may also comprise at least one known anticancer agent or pharmaceutically acceptable salts thereof, for the treatment of cancer.
• the disclosure is also directed to methods for the preparation of novel compounds of Formulae I, IIa, IIb, III and IV or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates or prodrugs thereof.
• hydrogen (H) as used herein includes its isotopes D and T.
• alkyl refers to alkyl itself or a straight or branched chain radical of up to ten carbons.
• Useful alkyl groups include straight-chain or branched C 1 -C 10 alkyl groups, preferably C 1 -C 6 alkyl groups. In some embodiments, alkyl is C 1 -C 4 alkyl.
• Typical C 1 -C 10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups.
• alkylene refers to the alkyl as defined above, which is located between two other chemical groups and is used to connect the two other chemical groups.
• Typical alkylene groups include, but are not limited to, methylene, ethylidene, propylene and butylene.
• alkoxy refers to oxygen substituted by the above mentioned C 1 -C 10 alkyl groups, preferred C 1 -C 6 alkyl groups or C 1 -C 4 alkyl groups.
• the alkyl in alkoxy groups may be optionally substituted.
• Substituents of alkoxy groups include, but are not limited to, halogen, morpholinyl (including morpholino), amino (including alkylamino and dialkylamino), and carboxy (including esters thereof).
• amino group as described herein can be expressed as —NR′R′′, wherein R′ and R′′ each are independently hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or R′ and R′′ together with the N to which they are attached form an optionally substituted 4-7 membered cyclic amino group, wherein the cyclic amino group optionally comprises one or more (such as 2, 3) additional heteroatoms selected from O, and S.
• Preferred amino groups include NH 2 and the amino groups in which at least one of R′ and R′′ is a C 1 -C 6 alkyl group.
• aryl as used herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms. Aryl may be substituted by one or more substituents as described herein.
• Useful aryl groups include C 6 -C 14 aryl groups, preferably C 6 -C 10 aryl groups.
• Typical C 6 -C 14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulyl, biphenyl, biphenylene and fluorenyl.
• Useful cycloalkyl groups are C 3 -C 8 cycloalkyl.
• Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• C 3 -C 8 cycloalkyl may be substituted by one or more substituents as described herein.
• Useful halo or halogen groups include fluoro, chloro, bromo and iodo.
• Useful acylamino groups are any C 1 -C 6 acyl (alkanoyl) attached to an amino nitrogen, e.g., acetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted C 1 -C 6 acylamino groups, e.g., benzoylamido.
• Useful acyl groups include C 1 -C 6 acyl groups, such as acetyl.
• Acyl may be optionally substituted by group selected from aryl and halo, wherein the aryl may be optionally substituted. When acyl is substituted by halo, the number of halogen substituents may be in the range of 1-5. Examples of substituted acyls include chloroacetyl and pentafluorobenzoyl.
• heterocyclic group refers to a saturated or partially saturated 3-7 membered monocyclic group, 7-10 membered bicyclic group, spiro group or bridged-ring group, which consists of carbon atoms and one to four heteroatoms independently selected from O, N, and S, wherein the nitrogen and/or sulfur heteroatoms can be optionally oxidized and the nitrogen can be optionally quaternized.
• heterocyclic group also includes the fused heterocycles of the bicyclic ring system in which any of the above-defined heterocycles is fused to a benzene ring.
• the heterocycle can be substituted on carbon atom or nitrogen atom if the resulting compound is stable.
• Heterocyclic group may be substituted by one or more substituents as described herein.
• Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl (such as morpholino), thiomorpholinyl (such as thiomorpholino), isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, azetidinyl, tetronoyl and tetramoyl, which may be optionally substituted by one or more substituents as described herein.
• heteroaryl refers to a group having 5 to 14 ring atoms, with 6, 10 or 14 ⁇ electrons shared in the ring system. Ring atoms of the heteroaryl are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. Heteroaryl may be substituted by one or more substituents as described herein.
• Useful heteroaryl groups include thienyl (thiophenyl), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl, including but not limited to 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazin
• heteroaryl group contains a nitrogen atom in a ring
• nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
• the alkyl, cycloalkyl, alkylene, alkoxy, acylamino, carbonyl, heterocyclic group, aryl or heteroaryl as described in any embodiment herein may be substituted by one or more (such as 1, 2, 3, or 4) substituents selected from the group consisting of: halo, cyano, nitro, hydroxy, carboxyl, C 1 -C 6 acylamino, C 1 -C 6 alkoxy, aryloxy, C 1 -C 6 alkyl, C 1 -C 6 acyl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, heterocyclic group or heteroaryl and carbonyl, and the like.
• substituent(s) itself may also be optionally substituted.
• Preferred substituents include, but are not limited to, halo, carbonyl, C 1 -C 6 acylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkyl and C 1 -C 6 acyl.
• the disclosure provides compounds as represented in Formula I or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates or prodrugs thereof:
• a 0 , A 1 and A 2 are independently selected from N or CR a ;
• R 0 is selected from a group consisting of hydrogen, cyano, alkyl, alkoxy and carbonyl, wherein the alkyl, alkoxy and carbonyl may be optionally substituted;
• R 1 is selected from a group consisting of halo, hydroxy and an optionally substituted alkoxy
• R 2 -R 4 are independently selected from a group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, nitro, carbonyl and acylamino, wherein the alkyl, alkoxy, carbonyl and acylamino may be optionally substituted;
• R 5 is selected from a group consisting of hydrogen, an optionally substituted alkyl and an optionally substituted alkoxy;
• R 6 is selected from a group consisting of hydrogen, halo, and an optionally substituted alkyl
• L is a bond, —C(R b ) 2 —, O, S or NR b ;
• Z is a bond or an alkylene
• Q is an optionally substituted heterocyclic group
• R a is selected from a group consisting of H, an optionally substituted alkyl and halo;
• R b is independently selected from a group consisting of hydrogen and an optionally substituted alkyl.
• each alkyl is independently C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl; each alkylene is independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene; preferably, when an alkyl (including the alkyl in an alkoxy) is substituted, the substituent(s) may be selected from a group consisting of amino, cyano, hydroxy, nitro, halo and carboxyl, and the like, and the number of the substituent(s) may be 1-5.
• a substituted alkyl may be a hydroxy alkyl, a dihydroxy alkyl and a halogenated alkyl; substituted alkoxy may be a halogenated alkoxy, etc.
• substituent(s) are cyano, nitro and carboxyl, the number of substituent(s) are usually 1; when the substituent(s) are such as halo, the number of the substituent(s) may be up to 5 halogen groups according to the carbon chain length of the alkyl; examples of such substituent(s) are trifluoromethyl, pentafluoroethyl and the like.
• R a is H or C 1-3 alkyl; more preferably, A 0 and A 1 are N or CH; A 2 is N, CH or CCH 3 . More preferably, A 0 and A 1 are N; A 2 is CH.
• R 0 is cyano, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.
• R 1 is halo, hydroxy, C 1-3 alkoxy or halogenated C 1-3 alkoxy.
• R 2 -R 4 when R 2 -R 4 are substituted, the substituent(s) may be selected from a group consisting of hydroxy, halo and amino, and the like.
• Preferred R 2 -R 4 are independently hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or halogenated C 1-3 alkyl. More preferably, R 2 -R 4 are independently selected from a group consisting of hydrogen, halo, C 1 -C 3 alkyl and halogenated C 1-3 alkyl. In some embodiments, R 2 -R 4 each are hydrogen. In some embodiments, only one of R 2 -R 4 is halo, C 1 -C 3 alkyl or halogenated C 1-3 alkyl, preferably, the other groups of R 2 -R 4 are H.
• R 5 is hydrogen or C 1 -C 3 alkyl.
• R 6 is hydrogen or C 1 -C 3 alkyl.
• L is C 1-3 alkylene, O, S or NR b , preferred R b is hydrogen or C 1-3 alkyl.
• Z is C 1-3 alkylene, more preferably methylene.
• the substituent(s) on Q are selected from a group consisting of halo, hydroxy, amino, carboxyl, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclic group, and the like.
• the substituent(s) on the optionally substituted alkyl and alkoxy may be one or more substituents selected from a group consisting of amino, halo, hydroxy and carboxyl.
• the alkyl may be substituted by —NR′R′′, wherein R′ and R′′ are as defined herein, preferably are independently H or C 1 -C 6 alkyl;
• the substituent(s) on the optionally substituted aryl, heteroaryl and heterocyclic group may be one or more substituents selected from a group consisting of amino, halo, hydroxy, carboxyl, alkyl and alkoxy.
• the substituent(s) on Q are at the ortho, meta and/or para position to the connecting position, and not at the connecting position.
• heteroatom of Q may be selected from N, O and S.
• Q comprises 1-3 heteroatoms.
• Q is an unsubstituted saturated 3-7 membered heterocyclic group or a saturated 3-7 membered heterocyclic group substituted by 1-2 optionally substituted C 1-3 alkyls, wherein the substituent(s) are at the ortho, meta and/or para position to the connecting position, and not at the connecting position.
• Preferred heterocyclic groups include but are not limited to piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl (such as morpholino), thiomorpholinyl (such as thiomorpholino), tetrahydropyranyl and azetidinyl.
• Preferred Q includes the following groups:
• the compound as represented in Formula I of the disclosure may have the structure as represented in the following Formula IIa:
• a 0 is selected from N or CR a ;
• R 0 is selected from a group consisting of hydrogen, cyano, alkyl, alkoxy and carbonyl, wherein the alkyl, alkoxy and carbonyl may be optionally substituted;
• R 1 is selected from a group consisting of halo, hydroxy and an optionally substituted alkoxy
• R 2 -R 4 are independently selected from a group consisting of hydrogen, halo, alkyl, alkoxy, nitro, carbonyl and acylamino, wherein the alkyl, alkoxy, carbonyl and acylamino may be optionally substituted;
• R 5 is selected from a group consisting of hydrogen, an optionally substituted alkyl and an optionally substituted alkoxy;
• L is a bond, —C(R b ) 2 —, O, S or NR b ;
• Z is a bond or alkylene
• Q is an optionally substituted heterocyclic group, wherein, the substituent(s) are at the ortho, meta and/or para position to the connecting position and not at the connecting position;
• R a is selected from a group consisting of H, an optionally substituted alkyl and halo;
• R b is independently hydrogen or an optionally substituted alkyl
• each alkyl is independently C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl; each alkylene is independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene.
• the subsitutent(s) may be selected from a group consisting of amino, cyano, hydroxy, nitro, halo and carboxyl, and the like, and the number of the substituent(s) may be 1-5.
• a substituted alkyl may be a hydroxy alkyl, a dihydroxy alkyl or a halogenated alkyl; a substituted alkoxy may be a halogenated alkoxy, etc.
• the number of the substituent(s) are usually 1; when the substituent(s) are such as halo, the number of the substituent(s) may be up to 5 halogen groups according to the carbon chain length of the alkyl; examples of such substituents are trifluoromethyl and pentafluoroethyl, and the like.
• a 0 is N or CH.
• R 0 is cyano, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.
• R 1 is halo, hydroxy, C 1 -C 3 alkoxy or halogenated C 1-3 alkoxy, more preferably C 1-3 alkoxy or halogenated C 1-3 alkoxy.
• R 2 -R 4 when R 2 -R 4 are substituted, the substituent(s) may be selected from a group consisting of hydroxy, halo and amino, and the like.
• Preferred R 2 -R 4 are independently selected from a group consisting of hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and halogenated C 1-3 alkyl. More preferably, R 2 -R 4 are independently selected from a group consisting of hydrogen, halo, C 1-3 alkyl and halogenated C 1-3 alkyl.
• R 2 -R 4 each are hydrogen. In some embodiments, only one of R 2 -R 4 is halo, C 1 -C 3 alkyl or halogenated C 1-3 alkyl, preferably, the other groups are H.
• R 5 is hydrogen or C 1 -C 3 alkyl.
• L is C 1-3 alkylene, O, S or NR b , preferred R b is hydrogen or C 1-3 alkyl.
• Z is C 1-3 alkylene, more preferably methylene.
• Q is preferably piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl (such as morpholino), thiomorpholinyl (such as thiomorpholino), tetrahydropyranyl and azetidinyl, which are optionally substituted.
• the substituent(s) on Q are selected from a group consisting of halo, hydroxy, amino, carboxyl, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclic group, and the like.
• the substituent(s) on the optionally substituted alkyl and alkoxy may be one or more substituents selected from a group consisting of amino, halo, hydroxy and carboxyl, for example, alkyl may be substituted by —NR′R′′, wherein R′ and R′′ are as defined above, preferably are independently H or C 1 -C 6 alkyl; the substituent(s) on the optionally substituted aryl, heteroaryl and heterocyclic group may be one or more substituents selected from a group consisting of amino, halo, hydroxy, carboxyl, alkyl and alkoxy.
• the substituent(s) on Q are at the ortho, meta and/or para position to the connection position.
• heteroatom on Q may be selected from N, O and S.
• Q comprises 1-3 heteroatoms.
• Q is an unsubstituted saturated 3-7 membered heterocyclic group or a saturated 3-7 membered heterocyclic group substituted by 1-2 optionally substituted C 1-3 alkyls, wherein the substituent(s) are at the ortho, meta and/or para position to the connecting position, and not at the connecting position.
• Preferred heterocyclic groups include but are not limited to piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl (such as morpholino), thiomorpholinyl (such as thiomorpholino), tetrahydropyranyl and azetidinyl.
• Preferred Q includes the following groups:
• One group of the preferred compounds of the disclosure is represented as compounds of Formula IIb or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates or prodrugs thereof:
• R 0 -R 4 and L are as described in any embodiment of Formula I above;
• Q is an unsubstituted saturated 3-7 membered heterocyclic group, or a saturated 3-7 membered heterocyclic group substituted by 1-2 optionally substituted C 1-3 alkyls, wherein the substituent(s) are at the ortho, meta and/or para position to the connecting position, and not at the connecting position.
• R 0 is cyano, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.
• R 1 is halo, hydroxy, C 1 -C 3 alkoxy or halogenated C 1 -C 3 alkoxy.
• R 2 -R 4 are independently hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or halogenated C 1 -C 3 alkyl; more preferably, R 2 -R 4 are independently hydrogen, halo, C 1 -C 3 alkyl or halogenated C 1 -C 3 alkyl; in some embodiments, R 2 -R 4 each are hydrogen; in some embodiments, only one of R 2 -R 4 is halo, C 1 -C 3 alkyl or halogenated C 1-3 alkyl.
• L is C 1-3 alkylene, O, S or NR b
• preferred R b is hydrogen or C 1-3 alkyl.
• preferred heterocyclic groups in Q include but are not limited to piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl (such as morpholino), thiomorpholinyl (such as thiomorpholino), tetrahydropyranyl and azetidinyl.
• Preferred Q includes the following groups:
• One group of the preferred compounds of the disclosure is represented as compounds of Formula III or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates or prodrugs thereof:
• R 1, R 3 and Q are as described in any embodiment of Formulae I, IIa and IIb above.
• R 1 is halo, hydroxy, C 1 -C 3 alkoxy or halogenated C 1 -C 3 alkoxy.
• R 3 is hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or halogenated C 1 -C 3 alkyl; more preferably, R 3 is hydrogen, halo, C 1 -C 3 alkyl or halogenated C 1 -C 3 alkyl.
• Q is an unsubstituted saturated 3-7 membered heterocyclic group or a saturated 3-7 membered heterocyclic group substituted by 1-2 optionally substituted C 1-3 alkyls, wherein the substituent(s) are at the ortho, meta and/or para position to the connecting position, and not at the connecting position.
• Preferred heterocyclic groups in Q include but are not limited to piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl (such as morpholino), thiomorpholinyl (such as thiomorpholino), tetrahydropyranyl and azetidinyl.
• Preferred Q includes the following groups:
• * refers to the connecting position of the group to the rest of the compound.
• One group of the preferred compounds of the disclosure is represented as compounds of Formula IV or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates or prodrugs thereof:
• a 0 , A 1 , A 2 , R 0 -R 6 , L, and Z are defined as any of the above-mentioned embodiments;
• a 3 is CH or N
• ring Q is a 3-7 membered heterocyclic group
• R 7 is selected from a group consisting of halo, hydroxy, amino, carboxyl, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclic group;
• n is an integer selected from the group consisting of 0-3, preferably 0-2.
• ring Q is a 3-7 membered heterocyclic group containing 1 or 2 heteroatoms selected from a group consisting of O, S and N.
• ring Q is selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl (such as morpholino), thiomorpholinyl (such as thiomorpholino), tetrahydropyranyl and azetidinyl and the like.
• R 7 is a C 1 -C 3 alkyl. In some embodiments, n is 0.
• each alkyl is independently C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl; each alkylene is independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene; preferably, when an alkyl (including the alkyl in an alkoxy) is substituted, the substituent(s) may be selected from a group consisting of amino, cyano, hydroxy, nitro, halo and carboxyl, and the like, and the number of the substituent(s) may be 1-5.
• a substituted alkyl may be a hydroxy alkyl, a dihydroxy alkyl and a halogenated alkyl; substituted alkoxy may be a halogenated alkoxy, etc.
• substituent(s) are cyano, nitro and carboxyl, the number of substituent(s) are usually 1; when the substituent(s) are such as halo, the number of the substituent(s) may be up to 5 halogen groups according to the carbon chain length of the alkyl; examples of such substituent(s) are trifluoromethyl, pentafluoroethyl and the like.
• R a is H or C 1-3 alkyl; more preferably, A 0 and A 1 are N or CH; A 2 is N, CH or CCH 3 . More preferably, A 0 and A 1 are N; A 2 is CH.
• R 0 is cyano, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.
• R 1 is halo, hydroxy, C 1-3 alkoxy or halogenated C 1-3 alkoxy.
• R 2 -R 4 when R 2 -R 4 are substituted, the substituent(s) may be selected from a group consisting of hydroxy, halo and amino, and the like.
• Preferred R 2 -R 4 are independently hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or halogenated C 1-3 alkyl. More preferably, R 2 -R 4 are independently selected from a group consisting of hydrogen, halo, C 1 -C 3 alkyl and halogenated C 1-3 alkyl. In some embodiments, R 2 -R 4 each are hydrogen. In some embodiments, only one of R 2 -R 4 is halo, C 1 -C 3 alkyl or halogenated C 1-3 alkyl, preferably, the other groups of R 2 -R 4 are H.
• R 5 is hydrogen or C 1 -C 3 alkyl; more preferably, R 5 is hydrogen.
• R 6 is hydrogen, halo or C 1 -C 3 alkyl; more preferably, R 6 is hydrogen.
• L is C 1-3 alkylene, O, S or NR b , preferred R b is hydrogen or C 1-3 alkyl.
• Z is C 1-3 alkylene, more preferably methylene.
• the ring Q optionally substituted by —(R 7 ) n is selected from a group consisting of
• a 0 is N; A 1 is N; A 2 is CH; A 3 is CH; R 0 is cyano; R 1 is C 1 -C 3 alkoxy; R 2 is hydrogen; R 3 is hydrogen, halo, or C 1 -C 3 alkyl; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; L is O; Z is C 1-3 alkylene, more preferably methylene; ring Q is a unsubstituted saturated 3-7 membered heterocyclic group; preferably, the unsubstituted saturated 3-7 membered heterocyclic group is selected from a group consisting of piperidinyl, pyrrolidinyl, and thiomorpholinyl; and n is 0.
• stereoisomers including optical isomers.
• the disclosure includes all stereoisomers and the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
• examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl-glucamine.
• inorganic and organic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate
• inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl-glucamine.
• prodrugs of the compounds of the disclosure include the simple esters of carboxylic acid-containing compounds (e.g., those obtained by condensation with a C 1 -C 4 alcohol according to methods known in the art); esters of hydroxy-containing compounds (e.g., those obtained by condensation with a C 1 -C 4 carboxylic acid, C 3 -C 6 diacid or anhydride thereof such as succinic anhydride and fumaric anhydride, according to methods known in the art); imines of amino-containing compounds (e.g., those obtained by condensation with a C 1 -C 4 aldehyde or ketone according to methods known in the art); carbamate of amino-containing compounds, such as those described by Leu, et al. ( J. Med.
• the compounds of this disclosure may be prepared using methods known to those skilled in the art, or the novel methods of this disclosure. Specifically, the compounds of this disclosure with Formula I can be prepared as illustrated by the exemplary reaction in Scheme 1. The mixture of 1-(2-hydroxy-6-methoxyphenyl)acetophenone and N,N-dimethylformamide dimethyl acetal was reacted under heating to produce (2E)-3-(dimethylamino)-1-(2-hydroxy-6-methoxyphenyl)-2-propenyl-1-one.
• Triphenylphosphine and diisopropyl azodicarboxylate were stirred at low temperature in tetrahydrofuran, then added with 3-methoxy-2-(1,2-oxazol-5-yl)phenol and tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate, and reacted at room temperature to produce tert-butyl (2S)-2-[3-methoxy-2-(1,2-oxazol-5-yl)phenoxymethyl]morpholine-4-carboxylate.
• the compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 2.
• 1-(2-Hydroxy-6-methoxyphenyl)ethenone, p-methoxybenzyl chloride (PMBC1) and K 2 CO 3 were reacted in DMF at room temperature to produce 1-(2-methoxy-6-((4-methoxybenzyl)oxy)phenyl)ethan-1-one.
• the compounds of Formula I are kinase inhibitors, especially CHK1 kinase inhibitors. Therefore, the compounds of Formula I (including the compounds of Formulae IIa, IIb, III and IV as described herein) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, or prodrugs thereof can be used for the treatment of diseases, disorders and conditions associated with continuous activation of CHK1 or with high internal DNA damage or injury during DNA replication, or for the preparation of medicament for the treatment of diseases, disorders and conditions associated with continuous activation of CHK1 or with high internal DNA damage or injury during DNA replication.
• Cancer can be a solid tumor or a blood tumor, including but not limited to liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leuk
• the cancer is related to continuous activation of CHK1 or to high internal DNA damage or injury during DNA replication; the phrase “related to” means that it plays a role in the occurrence and development of cancer, such as leading to the occurrence of cancer, and/or promoting the development or metastasis of cancer.
• the disclosure also provides a method for the treatment or prevention of diseases, disorders and conditions associated with continuous activation of CHK1 or with high internal DNA damage or injury during DNA replication, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I (including the compounds of Formulae IIa, IIb, III and IV as described herein) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereoisomer, racemate, solvate, hydrate or prodrug thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula I (including the compounds of Formulae IIa, IIb, III and IV as described herein) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereoisomer, racemate, solvate, hydrate or prodrug thereof.
• the subject includes mammal, more specifically human.
• effective amounts of pharmaceutical preparations are administered to a patient exhibiting one or more of these symptoms.
• the pharmaceutic preparation comprises therapeutically effective concentrations of the compounds of Formula I (including the compounds of Formulae IIa, IIb, III and IV as described herein) for oral, intravenous, local or topical application, for the treatment of cancer and other diseases.
• the amounts are effective to ameliorate or eliminate one or more symptoms.
• An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate or in some manner relieve symptoms associated with a disease. Such amount may be administered as a single dosage or may be administered according to an effective regimen.
• the amount may cure the disease but, typically, is administered in order to ameliorate symptoms of a disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.
• a pharmaceutical composition comprising a compound of Formula I of the disclosure (including the compounds of Formulae IIa, IIb, III and IV as described herein) or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereoisomer, racemate, solvate, hydrate or prodrug thereof as a CHK1 inhibitor, and a pharmaceutically acceptable carrier.
• Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to treat a cancer comprising a compound of Formula I, IIa, IIb, III or IV of the disclosure, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereoisomer, racemate, solvate, hydrate or prodrug thereof as a CHK1 inhibitor, and at least one known anticancer agent or a pharmaceutically acceptable salt thereof.
• the at least one known anticancer agent or a pharmaceutically acceptable salt thereof includes other anticancer agents related to the mechanism of DNA damage and repair, including PARP inhibitors Olaparib, Niraprib, Rucaparib, Talazoparib and Senaparib; HDAC inhibitors Volinota, Romididesin, Papiseta and Bailesta; and so on.
• the at least one known anticancer agent or a pharmaceutically acceptable salt thereof also includes other anticancer agents related to cell division checkpoints, including CDK4/6 inhibitors, such as Palbociclib, ATM/ATR inhibitors, and so on.
• anticancer agents which may be used for anticancer combination therapy include, but are not limited to alkylating agents, such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin and carboplatin; topoisomerase I inhibitors, such as camptothecin, irinotecan and topotecan; topoisomerase II inhibitors, such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium and etoposide; RNA/DNA antimetabolites, such as 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine and methotrexate; DNA antimetabolites, such as 5-fluoro-2′-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate
• anticancer agents which may be used for anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, Venetoclax, Aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer treatment vaccine).
• the compound(s) of the disclosure may be administered together with at least one known anticancer agent in a unitary pharmaceutical composition.
• the compound(s) of the disclosure may be administered separately from at least one known anticancer agent.
• the compound(s) of the disclosure and at least one known anticancer agent are administered substantially simultaneously, i.e. all compound(s) or agent(s) are administered at the same time or one after another, provided that the compound(s) or agent(s) reach therapeutic concentrations in the blood at the same time.
• the compound(s) of the disclosure and at least one known anticancer agent are administered according to individual dosage regimens, provided that the compound(s) reach therapeutic concentrations in the blood.
• bioconjugate which functions as a kinase inhibitor that comprises a compound of the disclosure and is effective to inhibit tumor.
• the bioconjugate of the disclosure comprises or consists of the compound(s) of the disclosure and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, or growth factor, such as EGF or FGF, or cytokine, such as IL-2 or IL-4, or any molecule that can bind to cell surface.
• the antibodies and other molecules could deliver the compound(s) described herein to the targets, making it an effective anticancer agent.
• the bioconjugates could also enhance the anticancer effects of the therapeutically useful antibodies, such as trastuzumab or rituximab.
• Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to inhibit tumor comprising the CHK1 inhibitor of Formula I, IIa, IIb, III or IV or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereoisomer, racemate, solvate, hydrate or prodrug thereof, in combination with radiation therapy.
• the compound(s) of the disclosure may be administered at the same time or at a different time as the radiation therapy.
• Another embodiment of the present disclosure is directed to a pharmaceutical composition effective for post-surgical treatment of cancer, comprising the CHK1 inhibitor of Formula I, IIa, IIb, III or IV, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereoisomer, racemate, solvate, hydrate or prodrug thereof.
• the disclosure also relates to a method of surgically removing tumor and then treating the cancer of the mammal with the pharmaceutical composition of the disclosure.
• compositions of the disclosure include all pharmaceutical preparations which contain the compound(s) of the present disclosure in an amount that is effective to achieve its intended purpose. While individual needs are different, the skill of the art could determine optimal amounts of each component in the pharmaceutical preparations.
• the compound(s) or the pharmaceutically acceptable salts thereof may be administered to mammals orally at a dose of about 0.0025 to 50 mg per kg body weight per day. Preferably, from approximately 0.01 mg/kg to approximately 10 mg/kg body weight is orally administered. If a known anticancer agent is also administered, it is administered in an amount that is effective to achieve its intended purpose. The optimal amounts of such known anticancer agents are well known to those skilled in the art.
• the unit oral dose may comprise from approximately 0.01 to approximately 50 mg, preferably approximately 0.1 to approximately 10 mg of the compound(s) of the disclosure.
• the unit dose may be administered one or more times, with one or more tablets daily, each containing from approximately 0.1 to approximately 50 mg, conveniently approximately 0.25 to 10 mg of the compound(s) of the disclosure or solvates thereof.
• the compound(s) of the disclosure may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.
• the compound(s) of the disclosure may be administered as a raw chemical.
• the compound(s) of the disclosure may also be administered as part of a suitable pharmaceutical preparation containing pharmaceutically acceptable carriers (comprising excipients and auxiliaries).
• pharmaceutically acceptable carriers facilitate the manufacture of pharmaceutically acceptable preparations from the compound(s).
• the pharmaceutical preparations particularly oral preparations and those used for the preferred administration routes, such as tablets, lozenges, and capsules, as well as solutions suitable for injection or oral administration, contain from approximately 0.01% to 99%, preferably from approximately 0.25% to 75% of active compound(s), together with excipient(s).
• non-toxic pharmaceutically acceptable salts of the compound(s) of the present disclosure are also included within the scope of the present disclosure.
• Acid addition salts are formed by mixing a solution of the compound(s) of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
• Base addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methyl-glucamine and the like.
• a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methyl-glucamine and the like.
• the pharmaceutical preparations of the disclosure may be administered to any mammal, so long as they may experience the therapeutic effects of the compound(s) of the disclosure.
• mammals are humans and veterinary animals, although the disclosure is not intended to be so limited.
• compositions of the present disclosure may be administered by any means that achieve their intended purpose.
• administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
• administration may be by oral route.
• the dosage administered will be dependent upon the age, health, and weight of the subject, the combined therapy, frequency of treatment, and the desired therapeutic efficacy.
• the pharmaceutical preparations of the present disclosure can be manufactured in a known manner, e.g., by conventional mixing, granulating, dragee-making, dissolving, or lyophilizing.
• Pharmaceutical preparations for oral use may be obtained by combining the active compound(s) with solid excipient(s), optionally grinding the resulting mixture, adding suitable auxiliaries if desired or necessary, processing the mixture of granules, thereby obtaining tablets or lozenge cores.
• Suitable excipients are, in particular, fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, including maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
• fillers such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol
• cellulose preparations and/or calcium phosphates e.g. tricalcium phosphate or calcium hydrogen phosphate
• binders such as starch paste, including maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose
• disintegrating agents may be added, such as the above-mentioned starches and carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
• Auxiliaries are, in particular, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
• lozenge cores can be provided with suitable coatings against gastric juices.
• concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
• suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used.
• Dyes or pigments may be added to the tablets or lozenge coatings, e.g., a combination to recognize or characterize a dose of active compound(s) .
• Other pharmaceutical preparations which may be used orally, include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules may contain the active compound(s) in the form of granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate; and stabilizers.
• the active compound(s) are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin, in which stabilizers may be added.
• Suitable formulations for parenteral administration include aqueous solutions of the active compounds, e.g., aqueous solutions and alkaline solutions of water-soluble salts.
• suspensions of the active compounds as appropriate oily injection suspensions may be administered.
• Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400, or cremophor, or cyclodextrins.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran.
• suspension stabilizers may also be contained.
• compounds of the disclosure are provided in topical and parenteral formulations and are used for the treatment of skin cancer.
• the topical formulations of this disclosure can be formulated as oils, creams, lotions, ointments and the like by suitable carriers.
• suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than Cu).
• Preferred carriers are those in which the active ingredient(s) are soluble.
• Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired.
• transdermal penetration enhancers may be included in these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.
• Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water, which is mixed with the active ingredient(s) dissolved in a small amount of an oil, such as almond oil.
• an oil such as almond oil.
• a typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.
• Ointments may be formulated by mixing a solution of the active ingredient(s) in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool.
• a vegetable oil such as almond oil
• a typical example of such ointments is one which includes approximately 30% by weight of almond oil and approximately 70% by weight of white soft paraffin.
• the present disclosure also involves use of the compounds of the disclosure for the preparation of medicaments for the treatment of diseases, disorders and clinical symptoms related to continuous activation of CHK1 or to high internal DNA damage or injury during DNA replication.
• medicaments may include the above-mentioned pharmaceutical compositions.
• tert-butyl (2S)-2-[2-(2-cyanoacetyl)-3-methoxyphenoxymethyl]morpholine-4-carboxylate A mixture of tert-butyl (2S)-2-[3-methoxy-2-(1,2-oxazol-5-yl)phenoxymethyl]morpholine-4-carboxylate (1.50 g, 3.8 mmol) and potassium hydroxide (0.43 g, 7.7 mmol) in ethanol (15 mL) and water (5 ml) was stirred at room temperature for 16 hours.
• tert-butyl (2S)-2-[2-(5-amino-2H-pyrazol-3-yl)-3-methoxyphenoxymethyl]morpholine-4-carboxylate A mixture of tert-butyl (2S)-2-[2-(2-cyanoacetyl)-3-methoxyphenoxymethyl]morpholine-4-carboxylate (648 mg, 1.7 mmol) and hydrazine hydrate (0.35 mL, 2.5 mmol, 35%) in tetrahydrofuran (1 mL), water (1 mL) and methanol (2 mL) was stirred, to which was added acetic acid (0.10 mL, 1.58 mmol).
• the reaction mixture was stirred at 120° C. for 3 hours, and after cooled to room temperature, it was diluted with water (50 mL), and extracted with ethyl acetate (80 mL ⁇ 3). The organic phases were combined, washed with saturated brine (40 mL ⁇ 2), and dried with anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluting with methanol in dichloromethane (1-10%)) to obtain the target product (512 mg, 76% yield, grayish white solid). MS (ESI, m/z): 405 [M+H] + .
• reaction mixture was stirred under the protection of N 2 at 80° C. for 3 hours, and the obtained reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL ⁇ 3). The organic phases were combined, washed with saturated brine (40 mL ⁇ 2), and dried with anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluting with methanol in dichloromethane (1-10%)) to obtain the target product (154 mg, 68% yield, grayish white solid). MS (ESI, m/z): 508 [M+H] + .
• reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by reverse phase chromatography (XBridge Shield RP18 OBD column, 30 ⁇ 150 mm, 5 ⁇ m; mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: acetonitrile; UV 254 nm) to obtain the target compound (30 mg, 31% yield, grayish white solid).
• reverse phase chromatography XBridge Shield RP18 OBD column, 30 ⁇ 150 mm, 5 ⁇ m; mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: acetonitrile; UV 254 nm
• the compound of this example was prepared using a method similar to that of Example 1.
• Triphenylphosphate (342.44 mg, 1.31 mmol) was dissolved in THF (2 ml) at 25° C. The resulting colorless and clear solution was cooled to ⁇ 5° C. in acetone/ice bath, and diisopropyl azodicarboxylate (DIAD, 253.44 mg, 1.25 mmol, 243.69 uL) was added dropwise to the solution for 20 min, with the temperature maintained below 10° C.
• DIAD diisopropyl azodicarboxylate
• the compound of Example 4 was synthesized from the compound of Example 1 and Mel in DMF in the presence of K 2 CO 3 .
• the compound can also be synthesized by other methods known to those skilled in the art.
• Examples 5-50 were prepared using the synthesis methods similar to that of Example 1 or 2.
• the compounds can also be synthesized by other methods known to those skilled in the art.
• tert-butyl (3 S)-3-[[2-(3-amino-4-bromo-1H-pyrazol-5-yl)-3-methoxy-phenoxy]methyl]piperidine-1-carboxylate To a solution of tert-butyl (3S)-3-[[2-(3-amino-1H-pyrazol-5-yl)-3-methoxyphenoxy]methyl]piperidine-1-carboxylate (1.6 g, 3.98 mmol, the compound was prepared using a method similar to that of Example 1e) in ACN (32 mL) was added NBS (778.29 mg, 4.37 mmol). The mixture was stirred at 25° C. for 12 hrs.
• tert-butyl(3S)-3-[[2-[3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl]-3-methoxy-phenoxy]methyl]piperidine-1-carboxylate To a solution of tert-butyl (3S)-3-[[2-(3-amino-1H-pyrazol-5-yl)-3-methoxy-phenoxy]methyl]piperidine-1-carboxylate (Example 51c, 500 mg, 1.24 mmol) in DMSO (5 mL) was added DIPEA (481.66 mg, 3.73 mmol, 649.13 ⁇ L) and 5-chloropyrazine ⁇ 2-carbonitrile (520.05 mg, 3.73 mmol).
• tert-butyl (3S)-3-[[2-[4-bromo-3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl]-3-methoxy-phenoxy]methyl]piperidine-1-carboxylate To a solution of tert-butyl (3S)-3-[[2-[3[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl]-3-methoxy-phenoxy]methyl]piperidine-1-carboxylate (280 mg, 553.83 ⁇ mol) in ACN (10 mL) was added NBS (108.43 mg, 609.22 ⁇ mol).
• Examples 53-75 were prepared using the synthesis methods similar to that of Example 1 or 2.
• the compounds can also be synthesized by other methods known to those skilled in the art.
• tert-butyl 2-[[2-[3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl]-3-methoxyphenoxy]methyl]thiomorpholine-4-carboxylate 5-[[5-(2-hydroxy-6-methoxy-phenyl)-1H-pyrazol-3-yl]amino]pyrazine-2-carbonitrile (Example 3e, 300 mg, 973.10 ⁇ mol) was added to a mixture of tert-butyl 2-(hydroxymethyl)thiomorpholine-4-carboxylate (340.57 mg, 1.46 mmol, 1.5 eq) in Tol.
• the residue 1 was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 ⁇ 50 mm ⁇ 3 ⁇ m; mobile phase: [water (0.225% FA)-ACN]; B %: 15%-35%, 10 min) to give one title compound (76-A, 17.42 mg, 39.50 ⁇ mol, 25.74% yield, 96.03% purity) as light yellow solid.
• the residue 2 was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 ⁇ 50 mm ⁇ 3 ⁇ m; mobile phase: [water(0.225% FA)-ACN]; B %: 15%-35%, 10 min) to give the other title compound (76-B, 12.15 mg, 27.50 ⁇ mol, 17.91% yield, 95.84% purity) as light yellow solid.
• Examples 77-80 were prepared using the synthesis methods similar to that of Example 1 or 2 and isolated using the method similar to that of Example 76.
• the compounds can also be synthesized by other methods known to those skilled in the art.
• 76-B 90.5% 78 457.94 — — — 79 502.39 — — — 80 437.52 — — —
• CHK1 enzyme activity was measured using Promega's ADP-GloTM kinase assay kit (#V9101) in a 384-well plate (Corning, #4512). 2 ⁇ L of kinase CHK1 (#V1941, Promega), 1 ⁇ L of compound diluted with buffer, and 2 ⁇ L of ATP substrate was successively added to a 384-well plate (final concentration of CHK1 was 1 ng/well, ATP was 10 ⁇ M). The positive control wells contained CHK1, ATP and DMSO whereas the negative control wells contained ATP, DMSO without enzyme. The mixtures were centrifuged at 1000 rpm for 1 minute and kept in darkness at room temperature for 1 hour to react.
• Inhibition rate % (RLU of positive control ⁇ RLU of compound)/(RLU of positive control ⁇ RLU of negative control) ⁇ 100.
• Table 1 summarizes the inhibitory effects of compounds on CHK1 kinase activity at a concentration of 10 nM (Inh %).
• Table 2 summarizes the inhibitory effects of compounds on CHK1 kinase activity (IC 50 ).
• Example 1 9 12 13 14 28 31 35 37 38 39 40 41 43 44 45 46 IC 50 (nM) 0.84 0.97 0.72 0.45 0.69 0.3 0.38 1.78 0.77 0.52 0.2 0.88 0.85 1.17 0.93 1.57 0.59
• Example 48 54 56 59 62 63 65 66 67 68 70 76-A 76-B LY2606368 IC 50 (nM) 0.58 0.86 1.02 2.27 1.58 1.66 0.26 1.22 1.72 0.44 1.16 0.79 1.21 1.34
• Example 1 As determined by the CHK1 kinase experiment, the compound of Example 1 and its analogues have good inhibitory effect on CHK1 kinase.
• Newly revived HCC1806 cells (purchased from Guangzhou Genio) were cultured and passaged for at least three generations before use. Cells were used at 90% confluency for experiments. Cells were digested with trypsinase and centrifuged at 800 rpm for 5 minutes. The cell pellets were resuspended in fresh RPMI1640 medium and cells were counted. Cells were seeded on 96-well cell culture plates at 2000 cells/well and incubated overnight at 37° C., 5% CO 2 . The stock solutions of the test substances (including the test compounds and the reference compound) were serially diluted to 8 concentrations with DMSO at a ratio of 1:3.
• Table 3 summarizes the inhibitory effect (IC 50 ) of compounds on the proliferation of human breast cancer cell HCC1806.
• the compound of Example 1 and its analogues have good inhibitory effect on the proliferation of HCC1806 cell.
• SW1990 cells purchased from Shanghai Fuheng Biology
• SW1990 cells were cultured and passaged for at least three generations before use. Cells were used at about 90% confluency for experiments. Cells were digested with trypsinase and centrifuged at 800 rpm for 5 minutes. The cell pellets were resuspended in fresh DMEM medium and cells were counted. Cells were seeded on 96-well cell culture plates at 5000 cells/well and incubated overnight at 37° C., 5% CO 2 . The stock solutions of the test substances (including the test compounds and the reference compound) were serially diluted to 8 concentrations with DMSO at a ratio of 1:3.
• Table 4 summarizes the inhibitory effect (IC 50 ) of compounds on the proliferation of human pancreatic cancer cell SW1990.
• the compound of Example 1 and its analogues have good inhibitory effect on the proliferation of SW1990 cell.
• Newly revived LoVo cells (purchased from Shanghai Cell Institute) were cultured and passaged for at least three generations before use. Cells were used at 90% confluence for experiment. Cells were digested with trypsinase and centrifuged at 800 rpm for 5 minutes and the supernatant was discarded. The cell pellets were resuspended in fresh RPMI1640 medium and counted. Cells were seeded on 96-well cell culture plates at 5000 cells/well and incubated overnight at 37° C., 5% CO 2 . The stock solutions of the test substances (including the test compounds and the reference compound) were serially diluted to 8 concentrations with DMSO at a ratio of 1:3.
• Table 5 summarizes the inhibitory effect (IC 50 ) of compounds on the proliferation of human colon cancer cell LoVo.
• Example 1 6 7 9 10 11 14 19 20 24 25 26 27 28 29 31 IC 50 (nM) 15.5 192.4 30.1 4.4 23.0 >1000 19.2 31.2 >1000 70.8 103.7 102.7 83.8 42.5 >1000 5.6
• Example 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 IC 50 (nM) 25.6 26.0 64.9 21.2 807.2 28.8 3.2 1.0 6.6 5.1 66.6 1.6 18.0 9.5 13.3 533.3
• Example 48 50 51 53 54 55 56 57 58 59 60 61 62 63 64 65 IC 50 (nM) 5.4 35.2 >1000 72.0 16.2 153.1 22.3 105.5 913.2 60.8 553.8 97.0 18.0 40.2 322.9 7.3
• Example 66 67 68 70 72 75 76-A 76-B 77-A 77-B LY2606368 IC 50 (nM) 14.3 9.1 2.3 3.6 6.0 3.2 2.1 17.8 3.1 17.3 5.56
• the compound of Example 1 and its analogues have good inhibitory effect on the proliferation of LoVo cell.

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